6,7-ethylene and 6,7-substituted ethylene derivatives of the pregnane series



United States Patent 3,485,828 6,7-ETHYLENE AND 6,7-SUBSTITUTED ETHYLENEDERIVATIVES OF THE PREGNANE SERIES John A. Zrleric, Mexico City, Mexico,assignor to Syntex Corporation, Panama, Panama, a corporation of PanamaNo Drawing. Continuation-impart of application Ser. No. 544,849, Apr.25, 1966. This application Apr. 10, 1967, Ser. No. 629,370

Int. Cl. C07c 173/00, 169/50; A61k 27/00 US. Cl. 260-23955 20 ClaimsABSTRACT OF THE DISCLOSURE 6,7ethylene and 6,7-substituted ethylenederivatives of the pregnane, including the 19-nor pregnane, serieshaving progestational activity are prepared by the photochemicalcycloaddition of an olefin of the formula:

wherein A is hydrogen or fiuoro, and B is hydrogen, fluoro, chloro,methyl or phenyl, to a 3-keto-A -diene of the pregnane, or 19-norpregnane, series.

wherein Z is a carbon-carbon single bond or a carbon-carbon double bond;

R is hydrogen, chloro, fiuoro or methyl;

R is hydrogen, hydroxy or a hydrocarbon carboxylic acyloxy group of lessthan 12 carbon atoms;

R is hydrogen or methyl; R being methyl when Z is a carbon-carbon doublebond;

R is keto or the group in which R is hydrogen, tetrahydropyran-2'-yl ora hydrocarbon carboXylic acyl group of less than 12 carbon atoms, Rbeing keto when Z is a carbon-carbon double bond; A is hydrogen orfluore; and B is hydrogen, fiuoro, chloro, methyl or phenyl.

The wavy line 2 at C-6 and C-7 indicates both alpha and betaconfigurations for the 6,7-ethylene and 6,7-substituted ethylenederivatives of the pregnane series, i.e. the

60,7ot-6IhYl6I16 and 6a,7a-S11bStituted ethylene derivatives of thepregnane series along with the 65,7{3-ethylene and 66,7;3-substitutedethylene derivatives of the pregnane series. The wavy line i at C-6indicates both alpha and beta configurations for the R substituent.

The hydrocarbon carboxylic acyloxy groups of the present inventioncontain less than 12 carbon atoms and are of a straight, branched,cyclic or cyclic'aliphatic chain structure. This structure is saturated,unsaturated or aromatic and optionally substituted by functional groupssuch as hydroxy, ethoxy containing up to 5 carbon atoms, acyloxycontaining up to 12 carbon atoms, nitro, amino, halogeno, and the like.Typical esters thus include acetate, propionate, enanthate, benzoate,trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate,aminoacetate, ,B-chloropropionate, adamantoate, and the like.

The novel compounds of the present invention are progestational agentsand are useful in fertility control and the management of variousmenstrual disorders. These compounds can be administered via usualroutes, i.e. orally or parenterally, in pharmaceutically acceptablecompositions and at dosage rates of from 0.5 to 5 mg./ kg./ day.However, dosage rates below or above this range can be used, the mostfavorable dosage range being condi tioned upon the purpose for which itis administered and the response thereto.

The novel compounds of the present invention are prepared in accordancewith the following sequence;

Gin; CH3 o=o (|J=O 1....

." a NR3 R Z ooA I $133 CH3 0:0 (i=0 1.113 i s 1130 i R4 O- 11 ILLHI R i(|3o|A R ACCA B B 1'; 1'; (III) (IV) wherein R is the group B Re J.

in which R is hydrogen, tetrahydropyran-2-yl or a hydrocarbon carboxylicacyl group of less than 12 carbon atoms; and R R R R A and B are aspreviously defined.

In the practice of the present invention the starting material ofFormula I, i.e., an unsubstituted or appropri- 3 ately substituted3-keto-A -diene, and an olefin of the formula:

wherin each of A and B is as previously defined, are irradiated withultraviolet light in an inert organic solvent, such as benzene, dioxaneand the like or mixtures thereof, to effect the photochemicalcycloaddition of the olefin and thereby aflord the 6,7-ethylene or6,7-substituted ethylene cycloaddition product as shown by Formula II. Apreferred choice for the cycloaddition employs benzene as the inertorganic solvent and ultraviolet light of a Wavelength of about 270 toabout 330 m Preferably, the photochemical cycloaddition is performed atroom temperature for from about 1 to about 12 hours. Any suitable sourceof ultraviolet irradiation of a Wavelength of about 270 to about 330 mcan be employed for the photochemical cycloaddition reaction. Among suchsources are commercially available high pressure mercury lamps, such asa 70 watt Hanau lamp, a 200 watt Hanovia, and the like.

Under the above conditions, the photochemical cycloaddition of theolefin occurs at the 4,5- and 6,7-double bonds to afiord a mixture of4,5-ethyelne or 4,5-substituted ethylene and 6,7-ethylene or6,7-substituted ethylene products. The orientation of the resulting4,5-ethylene or substituted ethylene group with respect to the steroidnucleus is both alpha and beta, i.e., the products having the 40c,5ot,45,56; and 4/3,5a-configurations. The orientation of the resulting6,7-ethylene or 6,7-substituted ethylene group with respect to thesteroid nucleus is both alpha and beta, i.e., the products having the60:,7aand 6fi,7,B-configurati0ns, and the 60:,704-iSOII16I generallybeing the predominant product. The mixture of products is routinelyseparated by a conventional procedure, such as column chromatography toyield the 6a,7a-ethylene- 6;3,7,8-ethylene-, the 6a,7a-substitutedethyleneand 6,6,73- substituted ethylenederivatives of the presentinvention.

Subsequent to the photochemical cycloaddition a 3- keto-A -ene-6,7-cycloadduct of Formula II (wherein R =CH is treated with2,3-dichlrO-5,6-dicyanobenzoquinone in dioxane to aiford a novel3-keto-A -diene-6J- cyclo adduct of Formula III. In addition, a 3-keto-Aene-6,7-cyclo adduct of Formula II is selectively reduced with sodiumborohydride in isopropanol to afford a corresponding 3fl-hydroxy A ene6,7 cyclo adduct of Formula IV which is subsequently treated withdihydropyran and an acid catalyst such as p-toluenesulfonic acid eitheralone or in an inert organic cosolvent such as benzene or with ahydrocarbon carboxylic acid anhydride and pyridine to yield acorresponding Bp-(tetrahydropyran-2' yloxy) or a corresponding3/8-acyloxy) 6,7-

cyclo adduct, respectively, each of which is included in Formula IV.

As an alternative to the above outlined reaction sequence, the startingmaterial of Formula I can be selected from a compound containing a17u-hydroxy group and elaborations can be performed by conventionaltechniques subsequent to the photochemical cycloaddition. Thus, forexample, a 17a-hydroxy cyclo adduct of Formulas II, III or IV is treatedwith a hydrocarbon carboxylic acid anhydride and p-toluenesulfonic acidin an inert organic solvent such as benzene to afiord a corresponding17aacyloxy cyclo adduct.

As a secondalternative to the above outlined reaction sequence, the A-diene-3,20-dione starting material of Formula I can be reduced to acorresponding A -diene- 3,8,20-diol by treatment with a reducing agentsuch as sodium borohydride in an inert organic solvent such as methanol.The latter diol can then be selectively oxidized at C-3 such as bytreatment with manganese dioxide, 2,3- dichloro-S,6-dicyanobenzoquinoneand the like, to a corresponding d -diene-zO-hydroxy-3-one which isconverted by the photochemical addition reaction as describedhereinabove to a corresponding 6,7-cycloadduct-A -ene- 20-hydroxy-3-one.Subsequent to the photochemical reaction, the ZO-hydroxy group in thelatter 6,7-cycloadduct is oxidized to a corresponding 20-keto group suchas. e.g., with chromic oxide in pyridine.

As a further alternativeto preparing a 17u-hydroxycompound of FormulaII, a A -diene-17o 2l-dihydroxy- 3,20-dione is converted to acorresponding 17zx,20:20,2lbismethylenedioxy by conventional treatmentwith formaldehyde and hydrochloric acid. A thus-obtained ndiene-3-onewith the protecting group intact is converted by the photochemicaladdition reaction as described hereinabove to a corresponding6,7-cycloadduct-A -ene-3-one with the protecting group still intact.Subsequent to the photochemical cycloaddition the17a,21-dihydroxy-20-one side chain is regenerated by conventionaltreatment of the 17,20220,21-dismethylenedioxy protecting group withaqueous acetic acid. The free 21-hydroxy group in the thus-obtained6,7-cycloadduct-A -ene-170:,21 dihydroxy- 3,20 dione is treated byconventional techniques first with tosyl chloride, methanesulfonylchloride or the like, second with sodium iodide in acetic acid and thirdwith sodium metabisulfite in aqueous ethanol to aiiord allunsubstituted-l7a-hydroxy-6,7-cycloadduct of the present invention.

The d -diene starting materials of Formula I are conveniently preparedby treating the correspondin 3- ket0-A -ene compound with chloranil in asolvent, such as t-butanol, xylene or the like, under reflux for aperiod of l to 12 hours.

The following examples are set forth to illustrate but are not intendedto limit the scope of the present tnvention.

EXAMPLE 1 A mixture of 2.0 g. of pregna-4,6-diene-3,20-dione in ml. ofbenzene in a Pyrex container is irradiated with a 200 Watt high pressuremercury vapor lamp at room temperature for a period of several hourswhile bubbling ethylene through the solution. At the end of the reactiontime, which is followed by U.V. spectra, the reaction mixture isevaporated in vacuo to dryness to furnish a residue containing a4a,5oz-ethylene adduct, a 45,5;8-ethylene adduct, a 45,5a-ethyleneadduct, a 60,70L-6thYl6l'lfi adduct, and a 6fl,7fi-ethylene adduct. Theresidue is sep arated by chromatography on silica eluting with ethylacetatezbenzene to yield 6a,7a-ethylenepregn-4-ene-3,20- dione and6B,7/3-ethylenepregn-4-ene-3,20-dione, each or which is recrystallizedfrom methanolzmethylene chloride.

Utilizing the same procedure, the following starting materials, namely6-chloropregna-4,6-diene-3 ,ZO-dione; 6-chl0ro-l9-nor-pregna-4,6-diene-3,20-dione; 6-fluorol 6u-methylpregna-4,6-diene-3,ZO-dione; 6,16u-dimethyl-l9-norpregna-4,6-diene-3,ZO-dione;19-norpregna-4,6-diene-3,20-dione;17a-hydroxy-19-norpregna-4,6-diene-3,20-dione;l6u-methylpregnal,6-diene-3,20-dione;16a-methyll9-norpregna-4,6-diene-3,20-dione17u-acetoxypregna-4,6-diene-3,ZO-dione;17ot-acetoxyl9-norpregna-4,6-diene-3 ,ZO-dione;l6a-methyl-17a-acetoxypregna-4,6-diene-3 ,20-dione;l6a-methyl-l'7a-acetoxyl 9-norpregna-4,6-diene- 3,20-dione; 6-chlorol6a-methylpregnal,6-diene-3 ,ZO-dione; 6-chloro-l6a-methyll9-norpregna-4,6-diene-3,20-dione;6-chloro-17ot-acetoxypregna-4,6-diene-3,20-dione;6-chloro-16u-methyl-17a-acetoxypregna-4,6-diene- 3,20-dione;17a-hydroxypregna-4,6-diene-3,20-dione; and 6-chloro-l6ot-methyll7ot-acetoxy-19-norpregna-4,6-

diene-3 ,ZO-dione; are converted to the 6a,7 flt-fithylel'lfi and613,7[i-ethylene derivatives, namely6,8-chloro-6a,7a-ethylenepregn-4-ene-3,ZO-dione, and the6u-chloro6,8,7B-isomer;6fi-chloro-6a,7a-ethylene-19-norpregn-4-ene-3,20-

dione, and the 6tx-chloro-6BJ5-isomer;6fi-fiuoro-6u,7a-ethylene-l6a-methylpregn-4-ene- 3,20-dione, and the6nt-fiuoro-6/i,7;6'isomer;6a,7a-ethylene-6,B,l6a-dimethyl-l9-norpregn-4-ene- 3,20-dione, and the6a-methyl-6B,7;3-isomer; 6a,7u-ethylene-l9-norpregn-4-ene-3,2O dione,and the 65,75-isomer; 6a7a-ethylene-17a-hydroxy-19-norpregn-4-ene-3,20-

dione, and the 6,8,7fl-isomer;6a,7a-ethylene-16ot-methylpregn-4-ene-3,ZO-dione, and the 613,75-isomer;6a,7a-ethylene-16u-methyl-19-norpregn-4-ene-3,20-

dione, and the 66,75-isomer;6a,7a-ethylene-17a-acetoxypregn-4-ene-3,20-dione, and

the 65,7[3-isomer; 6a7a-ethylene-17a-acetoxy-19-norpregn-4-ene-3,20-

dione, and the 65,7,8-is0mer;GOLJmMhYleIIB-l6a1n6lhyl-l7uc-tlC6tOXYPI6g1l-4-8I16- 3,20-dione, and the6,8,7fl-isomer; 6a,7a-ethylene-16a-methyl-l7a-acetoxy-l9-norpregn-4-ene-3,20-dione, and the 65,7fl-isomer; 6fi-chloro-6Dh-ethylene-l7wacetoxypregn-4-ene-3,20-

dione, and the 6a-chloro-6B,7fi-isomer;6B-chloro-6a,7x-ethylene-l6a-methyl-l9-norpregn-4- ene-3,20-dione, andthe 6a-ch1oro-6B,7fi-isomer;6,13-chloro-6a,7a-ethylene-l7a-acetoxypregn-4-ene-3,20-

dione, and the 6e-chloro-65Jfl-isomer;6,8-chloro-6a,7a-ethylene-16a-methyl-l7a-acetoxypregn-4-ene-3,20-dione,and the 6a-chloro- 56,7,8-isomer;6a,7a-ethylene-17a-hyroxypregn-4-ene-3,20-dione, and

the 65,7,8-isomer; and6fi-chloro-mafia-ethylene-16a-methyl-l7a-acetoxy-l9norpregn-4-ene-3,ZO-dione, and the 6a-chl0r0- 6,8 7B-isomer,respectively.

EXAMPLE 2 Utilizing the procedure of Example 1 with the exception ofsubstituting the following olefins, namely tetrafiuoroethylene,1,2-difiuoroethylene, butene-Z, 2,3 difiuorobutene-Z, and1,2-dichloro-1,Z-difiuoroethylene in place of ethylene, the startingmaterials 6-dehydroprogesterone and then 6-dehydro-19-n0rpr0gesteroneare converted to the following final products, namely6a,7a-tetrafiuoroethylenepregn-4-ene-3,ZO-dione, and the 65,7;3-isomer;

6a,70-( 1,2'-difluoro ethylenepregn-4-ene-3,ZO-dione,

and the 6,8,7B-isomer;

6a,7a-(1',2'-dimethyl)ethylenepregn-4-ene-3,ZO-dione,

and the 66,7/3-isomer;

6a,7 x-(1,2-difluoro-1,2'-dimethyl)ethylenepregn-4- ene-3,20dione, andthe 65,75-isomer;

6a,70z-( 1,2-dichloro-1,2-difiuoro)ethylenepregn-4- ene-3,20-dione, andthe 613,719-isomer;

6aflu-tetrafluoroethylene-l9-norpregn-4-ene-3,ZO-dione,

and the 65,75-isomer;

6a,7a-( 1,2'-difluoro)ethylene-19-norpregn-4-ene-3,20-

dione, and the 65,75-isomer;

601,7 a-( 1,2'-dimethyl) ethylene-19-norpregn-4-ene-3,20-

dione, and the 6,6,75-isomer;

6a,7 z( l',2-difluorol ,2-dimethyl) ethylenel9-norpregn-4-ene-3,ZO-dione, and the 66,75- isomer; and

EXAMPLE 3 A mixture of 2.0 g. of 17m,2l-dihydroxypregna-4,6-dien-3,20-dior1e in 140 ml. of benzene in a Pyrex container isirradiated at room temperature for a period of several hours whilebubbling ethylene through the solution. At the end of the reaction time,which is followed by the U.V. spectra, the reaction mixture isevaporated in vacuo to dryness to furnish a residue containing a 4:1,Sat-ethylene adduct, a 45,5,8-ethylene adduct, a 4B,5ocethylene adduct,a 6a.,7a.-ethylene adduct and a 65,7,8- ethylene adduct. The residue isseparated by chromatography on silica eluting with ethyl acetate:benzeneto yield 6a,7x ethylene-l70;,21-dihydroxypregn-4-en-3,2O-dione, and6fl,75-ethylene 1704,21 dihydroxypregn-4-en-3,20- dione, each of whichis recrystallized from methanol: methylene chloride.

A mixture of 1.34 g. of6tx,7u-ethylene-17a,21-dihydroxypregn-4-ene-3,ZO-dione, 0.38 ml. ofmethanesulfonyl chloride and 10 ml. of pyridine is allowed to stand atroom temperature for 16 hours and is then poured into ice water. Themixture is extracted several times with methylene chloride. The combinedmethylene chloride extracts are Washed with 2 N hydrochloric acid,aqueous potassium bicarbonate solution, and saturated aqueous sodiumchloride solution, dried over magnesium sulfate and evaporated todryness. This resulting residue and 3.6 g. of sodium iodide is added toml. of acetone, and boiled for 40 minutes. The mixture is thenevaporated to dryness under reduced pressure leaving a residue which isthen extracted several times with methylene chloride. The combinedextracts are washed With saturated aqueous sodium chloride solution,dried over magnesium sulfate and evaporated to dryness. A suspension ofthe thus-obtained residue and 2.6 g. of sodium metabisulfite in 300 ml.of 80% aqueous ethanol is heated at reflux for one hour and thenevaporated under reduced pressure at a temperature below 45 C. Theresidue is partitioned between water and methylene chloride and thephases are then separated. The organic phase is washed with saturatedaqueous sodium chloride solution, dried, and evaporated to dryness toyield 60L,7OL- ethylene-17u-hydroxypregn-4-ene-3,ZO-dione which can befurther purified through recrystallization from acetone:hexane.

By repeating the latter steps of the above procedure, with 65,75ethylene-:21-dihydroxypregn-4-en-3,20- dione, there is obtained thecorresponding 65,7B-ethylene- 17a-hydroxypregn-4-ene-3,20-dione.

Utilizing the above procedure and l7ot,2l-dihydroxy-19-norpregna-4,6-diene-3,20-dione as the starting material, there isobtained the corresponding 19-nor compound, namely60:,704-6thYl61'16-17ml'1y(l1'OXy 19 norpregn-4-ene-3,20

dione; and

65,7/3-ethylene-17ot-hydroxy 19 norpregn-4-ene-3,20-

dione, respectively.

In a similar fashion, tetrafluoroethylene is treated separately witheach starting material of this example to afford the 60,7mand6flflfi-tetrafiuoroethylene-17ot-hydroxypregn-4-ene-3,ZO-diones, and the611,7:1- and 618,75- tetrafiuoroethylene-l7a.-hydroxy-l9-norpregn 4ene-3, 20-diones.

EXAMPLE 4 A mixture of 1 g. of 6a,7a-ethylene-17a-hydroxypregn-4-ene-3,20-dione, 1 g. of p-toluenesulfonic acid monohydrate, 50 ml. ofacetic acid and 25 ml. of acetic anhydride is allowed to stand at roomtemperature for 24 hours, and then poured into water and stirred. Thismixture is then extracted several times with methylene chloride, and thecombined methylene chloride extracts are dried and evaporated to drynessto yield 6a.,7ot-ethylene-17m-acetoxypregn-4-ene-3,ZO-dione which isrecrystallized from acetonezether.

By repeating the above procedure with 6,3,75-ethylene-17a-hydroxypregn-4-ene-3,20-dione, there is obtained the corresponding65,75 ethylene-l7aacetoxypregn-4-ene-3, ZO-dione.

Utilizing the above procedure, other novel 17a-hydroxy compoundsdescribed herein, e.g. see Example 3, are

7 converted to their corresponding 17a.-acetoxy derivatives, among whichare the following:

6m,7a-tetrafluoroethylene 17m acetoxypregn-4-ene-3,20-

dione;

6a,7or-ethylene-17a-acetoxy 19 norpregn-4-ene-3,20-

dione; and

6a,7ot-tetrafluoroethylene 17a acetoxy-19-norpregn-4- ene-3,20-dione.

By repeating the above procedure with the 65,7,8- isomers of the abovestarting materials, there are obtained the corresponding 65,7,6-finalproducts.

Utilizing the same procedure, but substituting caproic anhydride andthen enanthic anhydride for acetic anhydride, there are obtained thecorresponding 17oz.- caproates and 17ot-enanthates.

EXAMPLE A solution of 200 mg. of 611,7ot-ethylenepregn-4-ene- 3,20-dionein 32 ml. of anhydrous isopropanol and 25 mg. of sodium borohydride isstirred at room temperature for 15 hours. One-hundred ml. of water isadded and the resulting suspension extracted several times with ether.The ether extracts are combined, dried over sodium sulfate andevaporated to dryness under reduced pressure to yield3,8-hydroxy-6a,7a.-ethylenepregn-4-en-20-one which can be furtherpurified by recrystallization from ether.

Two milliliters of dihydropyran are added to a solution of 1 g. of3B-hydroxy-6ot,7a-ethylenepregn-4-en-20-one in 15 ml. of benzene. About1 ml. is removed by distillation to remove moisture and 0.4 g. ofp-toluenesulfonyl chloride is added to the cooled solution. This mixtureis allowed to stand at room temperature for four days, and is thenwashed with aqueous sodium carbonate solution and water, dried andevaporated. The residue is chromatographed on neutral alumina, elutingwith hexane, to yield 3 3-(tetrahydropyran-Z-yloxy)-6a.,7u-ethylenepregn-4-en-20-one which is recrystallized from pentane.

By repeating the above procedure with the 65,75- isomer of the abovestarting material, there is obtained the corresponding3B-(tetrahydropyran-Z'-yloxy)6 8,75- ethylenepregn-4-en-20-one.

Utilizing the same procedure, the following starting materials, namely611,7u-tetrafluoroethylenepregn-4-ene-3,20-dione;

6m,7a-ethylene-l7a-acetoxypregn-4-ene-3,20-dione;

6a,7a-tetrafluoroethylene-17a-acetoxypregn-4-ene-3,20-

dione;

6a,7a-ethylene-6,B-methyl-17a-acetoxypregn-4-ene-3,20-

dione; and

6a,7 rx-( 1',2'-dimethy1) ethylenel9-norpregn-4-ene-3 ,20-

dione, are converted to the corresponding 3 B-tetrahydropyran-2'-yloxyderivatives, namely3/3-(tetrahydropyran-2-yloxy)-6a,7ot-tetrafiuoroethylenepregn-4-en-20-one;

3/5- (tetrahydropyran-2'-yloxy) -6oc,7ot-6thYl6H6-17aacetoxy-pregn-4-en-20-one;

313- (tetrahydropyran-2'-yloxy -6a,7a-tetrafluoroethylene-17a-acetoxypregn-4-en-20-one;

3 [3- (tetrahydropyran-2-yloxy) -6a,7a-ethylene-6fi-methyl-17a-acetoxypregn-4-en-20-one; and

3 ,8- tetrahydropyran-2'-yloxy) -6ot,7ot-( 1',2'-dimethyl)ethylene-l9-norpregn-4-en-20-one, respectively.

By repeating the above procedure with the 65,7fi-isomers of the abovestarting materials, there are obtained the corresponding 6fl,7,B-fina1products.

EXAMPLE 6 A solution of 200 mg. of 6a,7a-ethylenepregn-4-ene- 3,20-dionein 32 ml. of anhydrous isopropanol and 50 mg. of sodium borohydride isstirred at room temperature for 15 hours. One hundred ml. of water isadded and the resulting suspension extracted several times with ether.The

ether extracts are combined, dried over sodium sulfate and evaporated todryness under reduced pressure to yield3fi-hydroxy-6ix,7u-ethylenepregn-4-en-20-one which can be furtherpurified by recrystallization from ether.

A mixture of 1 g. of 3 fi-hydroxy-6a,7 a-BKhYI6IIEPIegD-4- en-20-0ne, 4ml. of pyridine and 2 ml. of acetic anhydride is allowed to stand atroom temperature for 15 hours. The mixture is then poured into icewater, and the solid which forms is removed by filtration, Washed withwater and then dried to yield 3B-acetoxy-6a,7ot-ethylenepregn-4-en-20-one which can be further purified by recrystallization fromacetonezhexane.

Utilizing the same procedure, the following starting materials, namely6ot,7a-tetrafluoroethylenepregn-4-ene-3,20-dione;6a,7a-ethylene-17a-acetoxypregn-4-ene-3,20-dione;6a,7a-tetrafluoroethylene-l7ot-acetoxypregn-4-ene-3,20-

dione; and 6a,7a-(1',2'-difluoro)ethylene-16a-methylpregn-4-ene-3,20dione; are converted to the corresponding 3 fl-acetoxy derivatives,namely 3l3-acetoxy-6a,7a-tetrafluoroethylenepregn-4-en-20-one;3B,17a-diacetoxy-6a,7a-ethylenepregn-4-en-20-one;3,6,17a-diacetoxy-6a,7ot-tetrafiuoroethylenepregn-4-en-20- one; and 3B-acetoxy6a,7a( l2-difiuoro) ethylene-16ot-methylpregn-4-20-one,respectively.

By repeating the above procedure with the 6,8,75-isomers of the abovestarting materials, there are obtained the corresponding 65,7,8-finalproducts.

EXAMPLE 7 A mixture of 0.5 g. of 60:,7ot-ethylenepregn-4-ene-3,20-dione, 10 ml. of dioxane and 0.35 g. of 2,3-dichloro-i6-dicyano-1,4benzoquinone is refluxed for ten hours. The reaction mixtureis then cooled, filtered and the organic filtrate is evaporated todryness. The resulting residue is dissolved in acetone and this solutionis then filtered through 10 g. of alumina. The acetone is removed byevaporation to yield 6a,7a-ethylenepregna-1,4-diene-3,20- dione which isfurther purified by recrystallization from acetone :hexane.

By repeating the above procedure with the 65,7,8-isomer of the abovestarting material, there is obtained the corresponding 65,7,8-isomer.

EXAMPLE 8 A mixture of 2 g. of 6-chloro-17u-acetoxypregna-4.6-diene-3,20-dione and 2 g. of stilbene in ml. of benzene in a Pyrexcontainer is irradiated with a 200 watt high pressure mercury vapor lampat room temperature for a period of three hours. After the end of thereaction time, the mixture is evaporated to dryness to furnish a residuecontaining a 4u,5a-(1,2-diphenyl)-ethylene adduct, 0.4B,5a-(1',2-diphenyl)ethylene adduct, a 6oc,7ot-(1',2'-dlphenyl)ethylene adduct, and a 6B,7fi-(1',2'-diphenyl) ethylene adduct.This residue is separated by chromatography on silica eluting with ethylacetatezbenzene to yield 65 chloro 60:,70: (1',2diphenyl)ethylene-17a-acetoxypregn-4-ene-3,20-dione and the6a-chloro-65,7/3- isomer, each of which is recrystallized from methanol:methylene chloride.

Utilizing the above procedure with the exception of substituting1',2'-dichloroethylene and then a,a-difluorostilbene for stilbene, thereare obtained the corresponding final products, namely6/3-ch1oro-6a,7a-(1',2-dichloro)ethylene-lh-acetoxypregn-4-ene-3,20-dione,and the 6a-ch1oro-6/3,7,B-

isomer; and

6B-chloro-6a,7a-(1',2-difluoro-1,2-diphenyl)ethylene-17a-acetoxypregn-4-ene-3,20-dione, and the 6a-chloro- 65,7;3-isomer,respectively.

9 EXAMPLE 9 A solution of l g. of sodium borohydride in 3 ml. of wateris added to an ice-cooled solution of 1 g. of 6-dehydroprogesterone in120 ml. of methanol and the mixture is then allowed to stand for 16hours at room temperature. The excess reagent is decomposed by additionof acetic acid and the solution is then concentrated to small volume invacuo and diluted with water. The product is extracted with ethylacetate and these extracts are washed with water, dried and evaporatedto yield 3,8,20-dihydroxypregna-4,6-diene which may be further purifiedby recrystallization from acetonezhexane.

One gram of 3fl,20-dihydroxypregna-4,6-diene in 100 ml. of chloroformwhich has been distilled over calcium chloride, is stirred for 18 hoursat room temperature with 10 g. of freshly precipitated manganesedioxide. The inorganic material is then removed by filtration and washedwith hot chloroform and the combined filtrate and washings areevaporated to yield 20-hydroxypregna-4,6-dien- S-one which may befurther purified through recrystallization from acetonerhexane.

A mixture of 2.0 g. of 20-hydroxypregna-4,6-dien-3- one in 140 ml. ofbenzene is irradiated with a 70 watt Hanan high pressure mercury vaporlamp with a Pyrex filter at room temperature for a period of severalhours while bubbling ethylene through the solution. At the end of thereaction time, which may be followed by the U.V. spectra, the mixture ofreaction products is evaporated in vacuo to dryness, chromatographed onsilica eluting with ethylacetatezbenzene to yield 6u,7a-ethylene-20-hydroxypregn-4-en-3-one which is recrystallized for methanolzmethylenechloride.

To a stirred solution of 1 g. of6u,7tz-ethylene-20-hydroxypregn-4-en-3-one in 10 ml. of acetone, cooledto C., is added under nitrogen a solution of 8 N chromic acid (preparedby mixing 26 g. of chromium trioxide with 23 ml. of concentratedsulfuric acid and diluting with water to 100 ml.) until the color of thereagent persists in the mixture. The mixture is then stirred for fiveminutes at 05 C. and diluted with water. The solid which forms iscollected by filtration, washed with water and dried under vacuum toyield 6a,7a-ethylenepregn-4-ene- 3,20-dione which may be furtherpurified by recrystallization from acetonezhexane.

EXAMPLE 10 To a solution of g. of 17a,21-dihydroxypregna-4,6-diene-3,20-dione in 200 ml. of chloroform are added 40 ml. of 37%aqueous formaldehyde and 5 ml. of concentrated hydrochloric acid. Themixture is stirred for 48 hours at room temperature and the two layersthen separated. The aqueous layer is extracted with chloroform and thecombined organic layer and chloroform extracts are washed with water toneutrality, dried over sodium sulfate and evaporated to dryness to yield17,20:20,2l-bismethylenedioxypregna-4,6-dien-3-one which isrecrystallized from methanolzether.

A mixture of 2.0 g. of17,20:20,21-bismethylenedioxypregna-4,6-dien-3-one in 140 ml. of benzeneis irradiated at room temperature for a period of several hours whilebubbling ethylene through the solution. At the end of the reaction time,which can be followed by the U.V. spectra, the mixture of reactionproducts is evaporated in vacuo to dryness, chromatographed on silicaeluting with ethylacetate2benzene to yield 6a,7m-ethylene-17,20:20,21-bismethylenedioxypregn-4-en-3-one which is recrystallized frommethanolzmethylene chloride.

One gram of 6a,7a-ethylene-17,20:20,21-bismethylenedioxypregn-4-en-3-onein 100 ml. of 80% acetic acid under nitrogen for seven hours. Themixture is then concentrated under vacuum to a small volume and pouredinto water. The solid which forms is collected by filtration, washedwell with water, dried and recrystallized from acetonezhexane to yield6a,7a-ethylene-17m,21-dihydroxypregn-4-ene- 3,20-dione.

A mixture of 1.34 g. of6a,7a-ethylene-l7u,2l-dihydroxypregn-4-ene-3,20-dione, 0.38 ml. ofmethanesulfonyl chloride and 10 ml. of pyridine is allowed to stand atroom temperature for 16 hours and is then poured into ice water andextracted with methylene chloride. The extracts are washed wth 2 Nhydrochloric acid, aqueous potassium bicarbonate solution, and saturatedaqueous sodium chloride solution, dried over magnesium sulfate andevaporated to dryness. This residue and 3.6 g. of sodium iodide is addedto 150 ml. of acetone, boiled for 40 minutes and evaporated to drynessunder reduced pressure. The residue is extracted with methylenechloride. These extracts are washed with saturated aqueous sodiumchloride solution, dried over magnesium sulfate and evaporated todryness. A suspension of the residue and 2.6 g. of sodium 'metabisulfitein 300 ml. of aqueous ethanol is heated at reflux for one hour and thenevaporated under reduced pressure at a temperature below 45 C. Theresidue is partitioned between water and methylene chloride and thephases are then separated. The organic phase is washed with saturatedaqueous sodium chloride solution, dried, and evaporated to dryness toyield 606,70C-6thY1- ene-17a-hydroxypregn-4-ene-3,20-dione which may befurther purified through recrystallization from acetonezhexane.

Utilizing the above procedure and 17a,21-dihydroxy-19-norpregna-4,6-diene-3,20-dione as the starting material, there isobtained the corresponding 19-nor compound, namely 6a,7aethylene-17a-hydroxy-19-norpregn-4-ene- 3,20-dione.

In a similar fashion, tetrafiuoroethylene is allowed to react with eachstarting material separately to afford 6:1,7tttetrafiuoroethylene 17ahydroxypregn-4-ene-3,ZO-dione and6a,7a-tetrafiuoroethylene-17a-hydroxy-19-norpregn- 4-ene-3,20-dione.

What is claimed is:

1. A compound of the formula:

wherein Z is a carbon-carbon single bond or a carboncarbon double bond;

R is hydrogen, chloro, fluoro or methyl;

R is hydrogen, hydroxy or a hydrocarbon carboxylic acryloxy group ofless than 12 carbon atoms;

R is hydrogen or methyl;

R is hydrogen or methyl; R being methyl When Z is a carbon-carbon doublebond; R is keto or the group in which R is hydrogen,tetrahydropyran-2'-yl or a hydrocarbon carboxylic acyl group of lessthan 12 carbon atoms; R being keto when Z is a carboncarbon double bond;

A is hydrogen or fluoro; and

B is hydrogen, fluoro, chloro, methyl or phenyl.

2. A compound according to claim 1 wherein R is hydrogen or chloro; R ishydrogen or acetoxy; each of A and B is hydrogen or fluoro; and R isketo.

3. A compound according to claim 2 wherein Z is a carbon-carbon singlebond; each of R R R and R is hydrogen; and each of A and B is hydrogen.

4. A compound according to claim 2 wherein Z is a carbon-carbon singlebond; each of R R and R is hydrogen; R is methyl; and each of A and B ishydrogen.

5. A compound according to claim 2 wherein Z is a carbon-carbon Singlebond; each of R and R is hydrogen; each of R and R is methyl; and eachof A and B is hydrogen.

6. A compound according to claim 2 wherein Z is a carbon-carbon singlebond; each of R R and R is hydrogen; R is methyl; and each of A and B ishydrogen.

7. A compound according to claim 2 wherein Z is a carbon-carbon singlebond; each of R R and R is hydrogen; R is acetoxy; and each of A and Bis hydrogen.

8. A compound according to claim 2 wherein Z is a carbon-carbon singlebond; each of R and R is hydrogen; R is acetoxy; R is methyl; and eachof A and B is hydrogen.

9. A compound according to claim 2 wherein Z is a carbon-carbon singlebond; each of R and R is hydrogen; R is acetoxy; R is methyl; and eachof A and B is hydrogen.

10. A compound according to claim 2 wherein Z is a carbon-carbon singlebond; R is hydrogen; R is acetoxy; each of R and R is methyl; and eachof A and B is hydrogen.

11. A compound according to claim 2 wherein Z is a carbon-carbon singlebond; R is chloro; each of R R and R is hydrogen; and each of A and B ishydrogen.

12. A compound according to claim 2 wherein Z is a carbon-carbon singlebond; R is chloro; each of R and R is hydrogen; R is methyl; and each ofA and B is hydrogen.

13. A compound according to claim 2 wherein Z is a carbon-carbon singlebond; R is chloro; R is hydrogen; each of R and R is methyl; and each ofA and B is hydrogen.

14. A compound according to claim 2 wherein Z is a carbon-carbon singlebond; R is chloro; each of R and R is hydrogen; R is methyl; and each ofA and B is hydrogen.

15. A compound according to claim 2 wherein Z is a carbon-carbon singlebond; R is chloro; R is acetoxy; each of R and R is hydrogen; and eachof A and B is hydrogen.

16. A compound according to claim 2 wherein Z is a carbon-carbon singlebond; R is chloro; R is acetoxy; R is hydrogen; R is methyl; and each ofA and B is hydrogen.

17. A compound according to claim 2 wherein Z is a carbon-carbon singlebond; R is chloro; R is acetoxy; R is methyl; R is hydrogen; and each ofA and B [5 hydrogen.

18. A compound according to claim 2 wherein Z is a carbon-carbon singlebond; R is chloro; R is acetoxy'. each of R and R is methyl; and each ofA and B is hydrogen.

19. A compound according to claim 1 wherein Z is a carbon-carbon singlebond; R is hydrogen or chloro; R is hydrogen or acetoxy; R is hydrogenor methyl: R is methyl; R is the group R- in which R istetrahydropyran-2'-yl; and each of A and B is hydrogen or fluoro.

20. A compound according to claim 1 wherein Z is a carbon-carbon singlebond; R is hydrogen or chloro; R is hydrogen or acetoxy; R is hydrogenor methyl; R is methyl; R is the group 1} RaO- in which R is acetyl; andeach of A and B is hydrogen or fluoro.

No references cited.

HENRY A. FRENCH, Primary Examiner U.S. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,485,828 Dated December 23, 1969 Inventor-(s) John A, Zderic It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column 1, lines 40 to 50, the formula should appear as follows:

Column 1, between lines 56 and 57, insert -R is hydrogen or methyl;-.

Column 3, line 7, "wherin' should read -wherein.

Column 3, line 26, "ethyelne" should read -ethylene-.

| Con t UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,485,828 Dated December 23, 1969 Inventor(s) John A, Zd ri PAGE 2 It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column 3, line 54, "3B-acyloxy) should read --3B-(acyloxy)-.

Column 5, line 19, "6on7on" should read --6d,7or.--,

Column 5, line 25, l7d-acetoxypregn" should read -l6dmethylpregn-.

Column 7, line 58, "acetoxy-pregn" should read --acetoxypregn--.

Column 8, line 57, '46, 5d" should read 6: 5B

Column 8, line 57, (l 2-diphenyl) should read -(l',2'-diphenyl)--.

Column 8, line 57, after "adduct, insert -a46,50L-(l',2'-diphenyl)ethylene adduct,-.

Column 9, line 31 "for" should read -from-.

Column 10, line 56, in Claim 1, "acryloxy" should read -acyloxy.

SI'GNED AND SEALED JUN 3 01970 om Anew Edward M Ir. An officer mm: B.SGH'UYLER, JR.

Commissioner of Patmtl

